Natural Killer (NK) cells are important for the control of viral infections and tumorigenesis. Upon activation, NK cells rapidly produce lytic molecules that are important for killing stressed, transformed, or infected target cells and effector cytokins that further stimulating the immune response. Post activation, these potent immune responses must be tightly regulated to maintain a productive response and rein in cytotoxic cells to avoid autoimmune disease. CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) is inhibitory receptor that is an essential modulator of T cell responses. Preliminary data from our lab shows, for the first time, that this important response regulator is expressed on NK cells during viral infection. However, it is unclear how CTLA-4 modulates NK cell responses. Further understanding of the underlying molecular mechanisms of NK cell responses will be useful in adapting and enhancing NK cell-based immunotherapy against cancer and infectious disease. To this end, we aim to elucidate the regulatory role of CTLA-4 on NK cell responses in vivo. Humans specifically lacking NK cells or NK cells effector function are particularly susceptible to human cytomegalovirus (HCMV). Though latent in a majority of the human population, it can cause life-threatening complications in newborns and immunosuppressed patients (e.g. AIDS patients, cancer patients undergoing radiation therapy, and transplant patients treated with immunosuppressive drugs). Using a mouse homolog (MCMV) of this disease, we will test the role of CTLA-4 in viral control by NK cells. Furthermore, we will investigate the role of CTLA-4 in tumor surveillance by NK cells using an established B16 mouse melanoma model, which is susceptible to NK cell eradication. B16 melanoma also mimics the intricacies of human tumor development, progress, and treatment strategies because it does not produce a productive immune response. Manipulation of CTLA-4 within the immune system is an emerging strategy of effective vaccination and tumor therapy. Therefore, understanding how CTLA-4 can modulate NK cell responses against both infectious disease and cancer will aid in future attempts to harness the immune system against these ailments in a clinical setting.